Materials are implanted into a human or animal body for a variety of purposes. Such implants include prosthetic devices, electrical leads, vascular grafts, and biosensors. Generally, most implants provoke a classic foreign body reaction. This reaction includes an acute inflammatory response of inflammatory cells and fibroblasts followed by a decrease in the acute inflammatory reaction and the production of a collagen. Eventually, the fibroblasts mature into fibrocytes, an avascular fibrous capsule is formed which walls off the implant, and the foreign body reaction becomes quiescent.
With certain types of implants, notably electrical leads and biosensors, the foreign body reaction with its resultant isolation of the implant from bodily tissues and fluids, is detrimental.
In the case of an electrical lead for stimulating tissue, the presence of a fibrotic capsule surrounding the lead dampens and decreases the output of the lead. This often can be overcome by increasing voltage. With biosensors, however, the situation differs. A biosensor may measure the presence of analytes in tissue fluid adjacent to the sensor. If an avascular fibrous capsule prevents the analyte from reaching the sensor, the sensor can no longer measure the level of the analyte even though the sensor itself is functioning properly. Increasing the sensitivity of the sensor, although somewhat analogous to increasing the voltage of an implanted electrical lead, does not correct the problem if the sensor is sealed off from tissue fluid containing the analyte.
Researchers have investigated various ways to try to reduce or eliminate the foreign body reaction around an implant and its resultant fibrous capsule and to increase neovascularization around the implant.
Beisang et al., Aesthetic Plastic Surgery, 16:83–90 (1992), reported that rough textured surfaces allow a mechanical bond and enhanced tissue adhesion at the host/implant interface which minimizes the thickness of a fibrous capsule. Den Braber et al, Biomaterials, 17:2037–2044 (1996), investigated various characteristics of microgrooved surfaces, including groove width, groove depth, and ridge width, to determine the morphology of fibroblasts on implants having varying grooved textures. They reported that on surfaces having a ridge width of 4.0 micrometers or less, fibroblasts were highly oriented, whereas with a ridge width of greater than 4.0 micrometers, the fibroblasts are arranged in a random cellular orientation. They further found that groove depth and groove width did not affect cellular orientation.
Brauker et al., J. Biomedical Materials Res., 29:1517–1524 (1995), investigated over 150 commercial membranes and concluded that the surface chemistry of an implanted membrane is not responsible for the degree of neovascularization around the implant. They concluded that membrane geometry, particularly the size of pores on a membrane, correlates with the degree of neovascularization adjacent to the membrane. They reported that implanted membranes having pores of 0.02 to 1 micrometer were bordered by a classical foreign body response without close vascular structures. In contrast, implanted membranes with pores of 3 or 5 micrometers, large enough to permit passage of host inflammatory cells, were bordered by a close association of vasculature. Brauker further disclosed that neither the structure of the pores nor the means of producing the pores is critical in the promotion of neovasculature. Both cellulosic and acrylic copolymer membranes, in which the pores are produced by solvent evaporation, and expanded polytetrafluoroethylene (ePTFE) membranes, in which the pores are produced by stretching, were effective in promoting neovascularization as long as the pores were of a sufficient size.
Sharkawy et. al., J. Biomedical Materials Res., 40(4):586–597 (1998) reported that PTFE implants having mean pore sizes of 5.0 and of 0.5 micrometers produced similar fibrotic capsules with little vascularity. They found that implanted polyvinyl alcohol (PVA) membranes having pore sizes of 5.0 and 60 micrometers were surrounded by sparse, randomly oriented tissue that resembled normal subcutaneous tissue and contained evidence of a granulomatous response. They further reported that implanted PVA membranes having a mean pore size of 700 micrometers were perceived by the body as being multiple implants as separate fibrous capsules surrounded each nodule of solid PVA between pores. From this data, Sharkawy concluded that mean pore size of 60 micrometers is optimal for inducing vascularity resembling granulation tissue. This objective might be achieved by providing adjacent to the sensor a scaffold of an open porous network with an average pore size in the range of cellular dimensions to incite fibrovascular ingrowth and sustained vasculature months after implantation.
Salzmann et al., J. Biomedical Materials Research, 34:463–476 (1997), reported that implanted expanded PTFE (ePTFE) membranes having an average internodal distance (pore size) of 60 micrometers produced more rapid endothelialization than did ePTFE membranes having an average pore size of 30 or of 100 micrometers. Further, the fibrous capsule surrounding the 60 micrometer pore size ePTFE was thinner than for the smaller and larger pore size ePTFE membranes.
Presently, microporous membranes are made by several methods, depending on the composition of the membrane. Porous PTFE membranes are made by expansion, that is by stretching, of the fabric of the membrane to form expanded PTFE (“ePTFE”). As shown in FIG. 1, ePTFE contains a tremendous variability of fibril 11 length, interfibrillar distance, size of islands or nodes 12, and internodal distance or pore size 13. FIG. 2 shows a porous polymer matrix in which the pores 15 are made by a gas foaming technique. The marked variability of the pore size and structure is evident in FIG. 2. Although with salt crystal poration and neutron bombardment the pore sizes are quite uniform, nonuniform pore spacing results in an unpredictable structure with an unpredictable tendency to promote neovascularization.
The variability of pore size and distribution in presently available membranes results in unpredictability of the foreign body reaction that is elicited by implantation of such membranes. Portions of such present-day membranes may or may not elicit the classical foreign body reaction with development of a fibrous capsule. Accordingly, an important need still exists for a membrane for a bioimplant that predictably encourages neovascularization and inhibits the formation of a fibrous capsule. This need is most strongly felt in regards to implanted analyte sensors, such as glucose sensors, that decline in accuracy within a brief span of days to weeks following implantation due to the development of a fibrous capsule around the implant that limits diffusion of the analyte to the sensor.
Additionally, although biological electricity sensors have been disclosed that included a microporous membrane covering the sensing surfaces, it appears that no similar analyte sensor has been taught. Analyte sensors are typically far more delicate than electricity sensors and so a much more complete level of neovascularization would be necessary to protect such a sensor.